The immune system and the central nervous system interact in a bidirectional manner. Activity of the central nervous system can direct marked changes in immune function. Likewise, peripheral inflammation is associated with pathological changes in motivational states and behavior, mood and cognition. Circadian and seasonal clocks in the hypothalamus yield high-amplitude rhythms in immune function and afford direct investigation of mechanisms mediating brain-to-immune interactions. Daily and seasonal rhythms in morbidity in response to inflammation are directly relevant to survival of numerous illnesses. Understanding how biological clocks engage changes in the immune system has implications for the treatment and management of chronic diseases (e.g., cancer, obesity) and acute bacterial and viral infections. The overall goal of the proposed research is to identify the mechanisms by which daily (circadian) and seasonal time information is communicated from the brain to the immune system. Siberian hamsters will be used as a model species specifically because they exhibit robust seasonal and circadian rhythms in innate and adaptive immune function which can be readily driven and synchronized by changes in the light-dark cycle. In this species, the amplitude of the seasonal cycle in several measures of immunity encompasses a range that would be clinically diagnostic of an immunocompromised state, yet hamsters exhibit these changes in immunity in the absence of co-morbid illness and in response to little more than a few hours' change in the light-dark cycle. Understanding the mechanisms by which time information drives changes in immune function will identify novel endogenous mechanisms by which the brain affects the immune system. This is a fundamentally-important issue which will inform treatments for seasonally-recurring illnesses in humans, and the causes of robust circadian rhythms in morbidity. These experiments will assess redistribution of blood leukocyte phenotypes, alterations in adaptive T cell-mediated immune function (DTH reactions), and changes in the magnitude of infection-induced innate inflammatory responses in experiments that seek to: (1) identify the cellular mechanisms by which changes in day length and melatonin control immune cell activity, (2) specify the role of thyroid hormone signaling in the genesis of seasonal changes in the immune system, (3) characterize the influence of the hypothalamic circadian pacemaker on daily rhythms in the immune system and on organismal-level immunocompetence, and (4) identify the output mechanisms that mediate coupling between the circadian clock and the immune system. The proximate causes of human seasonal and circadian rhythms in health and immune function remain largely unknown. Together, the work will afford major and novel biological insights into the mechanisms by which the nervous and endocrine systems guide the activity of the immune system.